The synthesis of B1 bradykinin (B1-BK) receptor is induced during inflammation in blood vessel muscular layers. This receptor is not present in normal conditions. This is in contrast with the B2-BK receptor which is normally present on many cell types or tissues. B1 receptor is present in the muscular layer of blood vessels and appears to be a factor involved in the vasoconstriction, the enhanced hydrostatic pressure and plasma leakage observed in an animal model of spontaneous hypertension (SHR) and in streptozotocin-induced diabetic rat model (STZ).
Many patent publications describe antagonists of bradykinin receptors. However, these antagonists all have an activity towards B2-receptors. If, amongst these agonists, one may find antagonists that may be converted into B1-antagonists by the action of carboxypeptidases, it remains that their verified activity towards B2-receptors indicates that such antagonists would not be selective for B1-receptors.
Recent reports point to an important role of kinin B1 receptors in physiopathology. Dray and Perkins1 have reviewed the possible implication of B1 receptors in various inflammatory states, tissue reactions and hyperalgesia, particularly the chronic phases of these experimental diseases. This has been further supported by some recent findings from Davis and coworkers2 in inflammatory hyperalgesia in the rat. Using B1 receptor antagonists, Alvarez et al.3 have suggested that B1 receptors may be present in spontaneous hypertensive rats whereas Chakir et al.4 and Zuccollo et al.5, have obtained strong evidence that B1 receptors may play a relevant role in streptozotocin-induced diabetes in rat and mouse models, respectively. It thus appears that B1 receptors are formed de novo and take part in the induction and/or the maintenance of pathological states. Or, as pointed out by Marceau6, “it is conceivable that B1 receptors can amplify the responses of injured tissues to kinins and, in some cases, take the relay of B2 receptors in chronic pathologies”. B1 receptor antagonists have been discovered in the late seventies7,8 but no substantial progress has been made in this area, despite the evidence of their usefulness in basic pharmacology and in various experimental pathologies.
We air ady demonstrated that capillary permeability was augumented in str ptozocin (STZ) diabetic rat model49. The vascular BK receptors of the portal veins of these animals have been shown to present enhanced contractibility and capillary permeability in response to B1-agonist desArg9BK, when compared to normal animals. This effect was abolished by B1-antagonist Lys(Leu8)desArg9BK while the B2-antagonist HOE140 had no effect thereon. A similar increased sensitivity to desArg9BK was observed in untreated SHR animals, prior to the establishment of hypertension, which was reversed by the same B1-antagonist. Even if these results indicate that B1-receptor is a target for a drug-preventive approach to diabetic or hypertensive vasculopathy, clinical testing becomes possible in as much as B1-antagonists capable of resisting to a very rapid enzymatic degradation are obtained. Substitutions in the natural B1-agonist desArg9-BK at amino acid residue proline have provided antagonists resistant to ACE degradation23. Further protection against amino peptidases is provided by adding non-hydrolysable amino acid residues at the N-terminal end. However, modifications at both residue 7 and N-terminal end also resulted in a loss of affinity for B1-receptor and even showed antagonistic activity towards B2-receptor.
Commercially available bradykinin antagonists also exist: D-Arg(Hyp3,Thi5,D-Tic7,Oic8)desArg9BK (S0765), (Hyp3,Thi5,D-TiC7,OiC8)desArg9BK (S1629) both developed by Hoechst, D-Arg(Hyp3,D-Hyp7(transpropyl),Oic8)desArg9BK (NPC18565) and D-Arg(Hyp3,D-Hyp7(trans thiophenyl), Oic8)desArg9BK (NPC18828), both developed by Scios Inc., are antagonists completely resistant to ACE degradation. However, none of them are selective for B1-receptor when tested in model tissues.
From the foregoing, it is apparent that there is a need for B1-antagonists which would be at least partially resistant to proteolytic enzymes, while the affinity and selectivity thereof for a B1-receptor would be preserved.